Incorporating susceptibility genetic variants of risk factors has been reported to enhance the risk prediction of polygenic risk score (PRS). However, it remains unclear whether this approach is effective for lung cancer. Hence, we aimed to construct a meta polygenic risk score (metaPRS) of lung cancer and assess its prediction of lung cancer risk and implication for risk stratification. Here, a total of 2180 genetic variants were used to develop nine PRSs for lung cancer, three PRSs for different histopathologic subtypes, and 17 PRSs for lung cancer-related risk factors, respectively. These PRSs were then integrated into a metaPRS for lung cancer using the elastic-net Cox regression model in the UK Biobank (N = 442,508). Furthermore, the predictive effects of the metaPRS were assessed in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial (N = 108,665). The metaPRS was associated with lung cancer risk with a hazard ratio of 1.33 (95% confidence interval: 1.27-1.39) per standard deviation increased. The metaPRS showed the highest C-index (0.580) compared with the previous nine PRSs (C-index: 0.513-0.564) in PLCO. Besides, smokers in the intermediate risk group predicted by the clinical risk model (1.34%-1.51%) with the intermediate-high genetic risk had a 6-year average absolute lung cancer risk that exceeded the clinical risk model threshold (≥1.51%). The addition of metaPRS to the clinical risk model showed continuous net reclassification improvement (continuous NRI = 6.50%) in PLCO. These findings suggest the metaPRS can improve the predictive efficiency of lung cancer compared with the previous PRSs and refine risk stratification for lung cancer.

Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

Objective: Medicine is critical for blood-pressure control in patients with type 2 diabetes mellitus (T2DM), for evaluation of treatment patterns and effects would offer baselines for future health services. Methods: A cross-sectional study was conducted from August 2018 to January 2021 in the urban-rural fringe zone of Suzhou City, Jiangsu Province, China. Blood pressure and antihypertensive medication use were collected from T2DM patients combined with hypertension (HTN). Using systolic blood pressure (SBP) and diastolic blood pressure (DBP) <140/85 mmHg as HTN controls, medicine usage patterns were analyzed. Results: Among the 931 T2DM patients with HTN, 333 (37.0%, 95% CI : 33.8%-40.2%) had HTN controlled with SBP and DBP of <140/85 mmHg. Partial following the medicine recommendations for HTN control were observed in this zone, and calcium channel blocker (CCB), angiotensin II receptor blocker (ARB), diuretics and beta-receptor blocker (Beta eta-blocker) were the most frequently used ones, especially for CCB and ARB, which accounted for 67% (625/931) and 55% (509/931), respectively. For combination usage, complete adherence to the recommendation was observed, ie, ARB + CCB and ARB + diuretics were listed as the top two, accounting 30% (282/931) and 16% (153/931), respectively. Combination therapies had HTN control rates ranging from 31.1% to 39.1%, lower than those of monotherapy (>40%). In monotherapies, CCB had control rate of 41.2% (115/279, 95% CI 35.4%-47.2%), higher than combination (31.9%, 105/329, 95% CI 26.9%-37.3%), as well as ARB; the single reagent had control rate of 42.0% (95% CI 33.7%- 50.7%), higher than combination (32.2%, 95% CI 27.4%-37.3%). Conclusions: More than 60% of T2DM patients had blood-pressures above the target level and the pattern of medications for HTN control in T2DM patients followed the recommendation of the authorities; however, the effects were not as expected, and more antihypertensive medicines or combinations would not raise the HTN control rate.

BACKGROUND:Insulin resistance has been reported to increase the risk of breast, prostate and colorectal cancer. However, the role of insulin resistance and its interaction with genetic risk in the development of lung cancer remains controversial. Therefore, we aimed to explore the association between a novel metabolic score for insulin resistance (METS-IR) and lung cancer risk. METHODS:A total of 395 304 participants without previous cancer at baseline were included. The Cox proportional hazards regression model was performed to investigate the association between METS-IR and lung cancer risk. In addition, a Mendelian randomization analysis was also performed to explore the causal relationship. The joint effects and additive interactions between METS-IR and polygenetic risk score (PRS) of lung cancer were also investigated. RESULTS:During a median follow-up of 11.03 years (Inter-quartile range (IQR): 10.30-11.73), a total of 3161 incident lung cancer cases were diagnosed in 395 304 participants. There was a significant association between METS-IR and lung cancer risk, with an HR of 1.28 (95% CI: 1.17-1.41). Based on the Mendelian randomization analysis, however, no causal associations were observed. We observed a joint effect but no interaction between METS-IR and genetic risk. The lung cancer incidence was estimated to be 100.42 (95% CI: 91.45-109.38) per 100 000 person-year for participants with a high METS-IR and PRS, while only 42.76 (95% CI: 36.94-48.59) with low METS-IR and PRS. CONCLUSIONS:High METS-IR was significantly associated with an increased risk of lung cancer. Keeping a low level of METS-IR might help reduce the long-term incident risk of lung cancer.

Background: To construct a meta polygenic risk score (metaPRS) based on PRS of lung cancer and related phenotypes. We also aimed to assess its prediction of lung cancer risk and implication for screening.Methods: A total of 2,180 genetic variants were used to develop a PRS for lung cancer, three PRSs for different histopathologic subtypes, and 17 PRSs for lung cancer-related risk factors, respectively. These PRSs were then integrated into a meta polygenic risk score (metaPRS) for lung cancer using the elastic-net Cox regression model with data from the UK Biobank (N=442,508). The predictive effects of the metaPRS were assessed in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial (N=108,665).Findings: The metaPRS was associated with lung cancer risk with a hazard ratio of 1·37 (95% confidence interval: 1·33-1·42) per standard deviation increased. The metaPRS showed the highest C-index (0·590) compared with the previous nine PRSs (C-index: 0·531-0·565) in the UK Biobank. Similarly, the metaPRS increased the C-index by 0·016-0·067 over the previous PRSs (C-index: 0·580 vs 0·513-0·564) in the PLCO. Higher metaPRS was associated with younger age at lung cancer diagnosis. Besides, individuals at intermediate predicted risk by clinical risk model (1·34%-1·51%) with the intermediate-high genetic risk had a six-year average absolute lung cancer risk exceeded the threshold clinical risk model risk≥1·51%. The addition of metaPRS to the clinical risk model showed continuous net reclassification improvement (continuous NRI=6·50%) in the PLCO cohort.Interpretation: The metaPRS improves the predictive efficiency of lung cancer compared with the previous PRSs, and refines risk stratification for lung cancer.Funding: National Natural Science Foundation of China; Excellent Youth Foundation of Jiangsu Province; Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer, Chinese Academy of Medical Sciences.Declaration of Interest: The authors have no conflicts of interest to declare.Ethical Approval: All participants provided written informed consent, and ethical approval for the UKB was obtained from the NHS National Research Ethics Service.

Background: Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer. Methods: Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs). Results: Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001). Conclusions: Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle. Funding: This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).

Key Clinical MessageWe reported a novel variant in Kallmann syndrome. It not only determines the clinical importance of whole exome sequencing for identification of genetic pathogenic variants, but also enriches the ANOS1 genetic spectrum of CHH patients in Chinese population.

This dataset provides a collection of 24 h electrocardiograph (ECG) signals, ECG analysis results based on circadian rhythm and R-peak detection, results of sleep quality assessment and clinical indicators of metabolic function acquired from 60 male type 2 diabetes mellitus (T2DM) inpatients. Upon admission, a fasting blood draw and urinary sample were obtained the next morning for routine glucose, lipid and renal panels. Subjects were also involved in investigation for diabetic complications. On the second day of hospitalization, subjects were monitored in hospital for 24-h ECG starting at 10 pm. Subjective sleep quality was assessed by Pittsburgh Sleep Quality Index and a brief sleep log was used to record sleep duration for the studied night. Objective sleep quality and sleep staging were assessed by cardiopulmonary coupling analysis. This dataset could be utilized to conduct conjoint research on the relationships among sleep, metabolic function, and function of cardiovascular system and autonomic nervous system derived from ECG analysis in T2DM, and further investigate the information in ECG signals based on circadian rhythm and physiological status, providing new insights into long term physiological signal processing.

Abstract Objective: In order to control blood glucose levels, anti-glycemic drugs are used in T2DM patients. However, with more drugs are approved and widely clinical used, it is important to explore the association between the number of hypoglycemic drugs usage and T2DM control. Methods: From August 2018 to January 2021, three health service centers (urban-rural fringe zone) participated in T2DM health management project offering basic public health service from hospitals in Suzhou, Jiangsu province. Glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) level, combined with detail information of the diabetic history and hypoglycemic drugs usage were collected during the carryout of the project. Basic information and clinical laboratory examinations were analyzed with Student’ t or t’ or chi-square test for univariate analysis. Multivariate analyses were used for exploring multiple variables. Results: The level of glycosylated hemoglobin (HbA1c) less than 7.0% were consider as well-controlled of T2DM and the control rate of the patients was 36.8% (434 / 1179, 95% CI 33.2% - 38.8%). Sulfonylureas, biguanides, glucosidase inhibitors and insulin were the most frequently used hypoglycemic drugs in T2DM patients in this region and the utilization rates of them were 65.5%, 66.4%, 17.7% and 19.1% in the uncontrolled patients and in controlled were 68.4%, 58.5%, 14.3% and 11.1%, respectively. Higher proportion of biguanides, glycosidase inhibitors and insulin in the uncontrolled patients were observed than that in the controlled (P <0.05). The proportions for one, two, or more than three hypoglycemic drugs used in the uncontrolled patients were 29.5%, 51.7% and 18.8%, in the controlled group was 45.6%, 46.1% and 8.2%, respectively. On the whole, the number of drugs used in the uncontrolled patients was higher than that in the controlled group (P <0.001). Factors including the course of diabetes, biguanides, glucosidase inhibitors, and insulin usage were associated with poor glycemic control according to multivariate regression analysis. Conclusions: Anti-glycemic drugs play important role in lowering blood glucose for T2DM patients, but more drugs (more numbers or larger dosage ) might not improve blood glucose control. Especially, for management of diabetic patients in the rural-urban fringe zone, related factors should pay more attention other than hypoglycemic drugs.

Most lung cancer risk prediction models were developed in European and North‐American cohorts of smokers aged ≥ 55 years, while less is known about risk profiles in Asia, especially for never smokers or individuals aged < 50 years. Hence, we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range.

Introduction: Autonomic nervous system (ANS) plays an important role in the exchange of metabolic information between organs and regulation on peripheral metabolism with obvious circadian rhythm in a healthy state. Sleep, a vital brain phenomenon, significantly affects both ANS and metabolic function.Objectives: This study investigated the relationships among sleep, ANS and metabolic function in type 2 diabetes mellitus (T2DM), to support the evaluation of ANS function through heart rate variability (HRV) metrics, and the determination of the correlated underlying autonomic pathways, and help optimize the early prevention, post-diagnosis and management of T2DM and its complications.Materials and methods: A total of 64 volunteered inpatients with T2DM took part in this study. 24-h electrocardiogram (ECG), clinical indicators of metabolic function, sleep quality and sleep staging results of T2DM patients were monitored.Results: The associations between sleep quality, 24-h/awake/sleep/sleep staging HRV and clinical indicators of metabolic function were analyzed. Significant correlations were found between sleep quality and metabolic function (|r| = 0.386 ± 0.062, p < 0.05); HRV derived ANS function showed strengthened correlations with metabolic function during sleep period (|r| = 0.474 ± 0.100, p < 0.05); HRV metrics during sleep stages coupled more tightly with clinical indicators of metabolic function [in unstable sleep: |r| = 0.453 ± 0.095, p < 0.05; in stable sleep: |r| = 0.463 ± 0.100, p < 0.05; in rapid eye movement (REM) sleep: |r| = 0.453 ± 0.082, p < 0.05], and showed significant associations with glycemic control in non-linear analysis [fasting blood glucose within 24 h of admission (admission FBG), |r| = 0.420 ± 0.064, p < 0.05; glycated hemoglobin (HbA1c), |r| = 0.417 ± 0.016, p < 0.05].Conclusions: HRV metrics during sleep period play more distinct role than during awake period in investigating ANS dysfunction and metabolism in T2DM patients, and sleep rhythm based HRV analysis should perform better in ANS and metabolic function assessment, especially for glycemic control in non-linear analysis among T2DM patients.

BackgroundEmerging evidence suggests a potential link between psychological distress (anxiety and depression) and lung cancer risk, however, it is unclear whether other factors such as tobacco smoking and genetic susceptibility modify the association.MethodsWe included 405,892 UK Biobank participants free of cancer at baseline. Psychological distress was measured using the Patient Health Questionnaire-4 (PHQ-4). A polygenic risk score (PRS) was calculated using 18 lung cancer-associated genetic loci. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsDuring a median follow-up of 7.13 years, 1754 lung cancer cases were documented. The higher score of psychological distress was associated with an increased risk of lung cancer (HRper 1-SD= 1.07, 95% CI: 1.02-1.11) after adjustment for smoking and other confounders. Mediation analysis revealed that 16.8% (95% CI: 13.0%-20.6%) of the distress-lung cancer association was mediated by smoking. Compared with never smokers with no distress, participants with heavy smoking and high distress had the highest risk of lung cancer (HR=18.57, 95% CI: 14.51-23.76). Both multiplicative and additive interactions were observed between smoking and psychological distress in lung cancer. Furthermore, the greatest relative increase in risk was observed among those with high genetic risk and high distress (HR=1.87, 95%CI: 1.50-2.33), and there was a significant additive interaction between the PRS and psychological distress.ConclusionOur results indicate that psychological distress was associated with an elevated risk of incident lung cancer, and such relation was modified by tobacco smoking and genetic susceptibility.

This article introduced the research design and main results of the article " Effect of Moderate and Vigorous Aerobic Exercise on Incident Diabetes in Adults with Obesity: A 10-Year Follow-up of a Randomized Clinical Trial" recently published in JAMA Internal Medicine, and addressed the scientific significance of the study. The importance of obesity management has been well discussed recently. This study investigated obesity management strategies for obese individuals and their long-term metabolic benefits.

目的 调查苏州高新区通安社区糖尿病患者的血糖、血压、血脂达标情况,分析相关危险因素,为后期对该社区糖尿病的防治提供依据.方法 收集2018年10月—2019年6月苏州通安社区的479例2型糖尿病患者的基本资料及血糖、血脂、血压等指标,分析该社区糖尿病的患病现况和危险因素.结果 研究对象的血糖、血压、血脂总达标率分别为43.84％、14.82％、39.25％,三者均达标率为2.92％,其中女性2型糖尿病患者的LDL-C的达标率明显低于男性,差异有统计学意义(P<0.05).女性糖尿病患者的病程、中心性肥胖比率和血脂水平均明显高于男性患者,腰围水平显著低于男性患者,差异有统计学意义(P<0.05).另外,病程与中心性肥胖是男性HbA1c、血压与LDL-C不达标的独立危险因素,女性血压不达标的独立保护因素(P<0.05);而年龄是男性血压与LDL-C不达标的独立危险因素,是女性HbA1c与LDL-C不达标的独立危险因素(P<0.05);而中心性肥胖是男性与女性HbA1c、血压与LDL-C不达标的独立危险因素(P<0.05).结论 苏州通安社区糖尿病患者的血糖、血压、血脂综合达标率低,需加大对城郊社区糖尿病患者管理的支持,尤其患者的中心性肥胖、血脂控制,并积极干预女性患者的血糖血压管理.

Chronological age only represents the passage of time, whereas biological age reflects the physiology states and the susceptibility to morbidity and mortality. The association between biological age and lung cancer risk remains controversial. Hence, we conducted a prospective analysis in the UK Biobank study and two-sample Mendelian randomization analysis to investigate this association. Biological aging was evaluated by PhenoAgeAccel, derived from routine clinical biomarkers. Independent of chronological age, PhenoAgeAccel was positively associated with the risk of overall and histological subtypes of lung cancer. There was a joint effect of PhenoAgeAccel and genetics in lung cancer incidence. In Mendelian randomization analysis, the genetically predicted PhenoAgeAccel was associated with the increased risk of overall lung cancer, small cell, and squamous cell carcinoma. Our findings suggest PhenoAgeAccel is an independent risk factor for lung cancer, which could be incorporated with polygenic risk score to identify high-risk individuals for lung cancer.

Context Relationships between insulin-like growth factor 1 (IGF-1) levels and cardiovascular disease (CVD) in the general population remain unclear. Objective This study aims to investigate the association of circulating IGF-1 concentrations with CVD from a population-based cohort study. Methods A total of 394 082 participants without CVD and cancer at baseline from UK Biobank were included with measurements of serum IGF-1 at baseline. Main outcomes were incidence of CVD, including CVD mortality, coronary heart disease (CHD), myocardial infarction (MI), heart failure (HF), and stroke. Results Over a median 11.6 years of follow-up, UK Biobank documented 35 803 incident CVD cases, including 4231 from CVD-related death, 27 051 from CHD, 10 014 from MI, 7661 from HF, and 6802 from stroke. Dose-response analysis showed a U-shaped relationship between IGF-1 levels and cardiovascular events. Compared with the third quintile of IGF-1, the lowest category of IGF-1 was associated with increased risk of CVD (hazard ratio 1.128; 95% CI, 1.093 to 1.164), CVD mortality (1.294; 1.181 to 1.418), CHD (1.118; 1.078 to 1.159), MI (1.071; 1.008 to 1.139), HF (1.185; 1.107 to 1.268), and stroke (1.149, 1.070 to 1.235); also, the highest category was associated with increased risk of CVD (1.056; 1.020 to 1.094), CVD mortality (1.111; 1.000 to 1.236), CHD (1.070; 1.028 to 1.114), MI (1.111; 1.041 to 1.187) and HF (1.098; 1.015 to 1.188) after multivariable adjustment. Conclusion This study indicates that both low and high levels of circulating IGF-1 are associated with increased risk of CVD in general population. These results highlight the importance of monitoring IGF-1 status on cardiovascular health.

BACKGROUND:The role of genetic background underlying the disparity of relative risk of smoking and lung cancer between European populations and East Asians remains unclear. METHODS:To assess the role of ethnic differences in genetic factors associated with smoking-related risk of lung cancer, we first constructed ethnic-specific polygenic risk scores (PRSs) to quantify individual genetic risk of lung cancer in Chinese and European populations. Then, we compared genetic risk and smoking as well as their interactions on lung cancer between two cohorts, including the China Kadoorie Biobank (CKB) and the UK Biobank (UKB). We also evaluated the absolute risk reduction over a 5-year period. RESULTS:Differences in compositions and association effects were observed between the Chinese-specific PRSs and European-specific PRSs, especially for smoking-related loci. The PRSs were consistently associated with lung cancer risk, but stronger associations were observed in smokers of the UKB [hazard ratio (HR) 1.26 vs 1.15, P  =  0.028]. A significant interaction between genetic risk and smoking on lung cancer was observed in the UKB (RERI, 11.39 (95% CI, 7.01-17.94)], but not in the CKB. Obvious higher absolute risk was observed in nonsmokers of the CKB, and a greater absolute risk reduction was found in the UKB (10.95 vs 7.12 per 1000 person-years, P <0.001) by comparing heavy smokers with nonsmokers, especially for those at high genetic risk. CONCLUSIONS:Ethnic differences in genetic factors and the high incidence of lung cancer in nonsmokers of East Asian ethnicity were involved in the disparity of smoking-related risk of lung cancer.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.